靶向抑制去泛素化酶USP7/USP47对Flt3-ITD突变及非突变急性髓系白血病细胞增殖和凋亡的影响  

Effects of targeted inhibition of deubiquitinase USP7/USP47 on proliferation and apoptosis of acute myeloid leukemia cells with or without Flt3-ITD mutation

作　　者：张倩钰 高宇昂 李欣 苏永锋 蔡博 王安 周杰 宁红梅 Zhang Qianyu;Gao Yu′ang;Li Xin;Su Yongfeng;Cai Bo;Wang An;Zhou Jie;Ning Hongmei(The PLA 307 Clinical College of Anhui Medical University,the Fifth Clinical Medical College of Anhui Medical University,Hefei 230032,China;Medical School of Chinese PLA,Beijing 100853,China;Department of Hematology,the Fifth Medical Center of Chinese PLA General Hospital,Beijing 100071,China)

机构地区：[1]安徽医科大学解放军307临床学院,安徽医科大学第五临床医学院,合肥230032 [2]解放军医学院,北京100853 [3]解放军总医院第五医学中心血液病医学部,北京100071

出　　处：《中华微生物学和免疫学杂志》2024年第3期217-224,共8页Chinese Journal of Microbiology and Immunology

基　　金：国家重点研发计划(2020YFA0112401);国家自然科学基金(82122004,82070104);国家重点实验室开放课题(SKLP-O201804)。

摘　　要：目的探讨去泛素化酶USP7/USP47特异性小分子抑制剂(Cat.No.1247825-37-1)对Flt3-ITD突变及非突变急性髓系白血病(acute myeloid leukemia,AML)细胞增殖和凋亡的影响。方法采用ATP法检测1247825-37-1对Flt3-ITD突变AML细胞系MOLM13和MV4-11,以及Flt3-ITD非突变AML细胞系THP-1的影响;检测1247825-37-1对患者原代Flt3-ITD突变及非突变AML细胞增殖活性的影响;流式细胞术检测不同浓度1247825-37-1对Flt3-ITD突变及非突变AML细胞系凋亡的影响。结果与对照组相比,1247825-37-1对Flt3-ITD突变及非突变的AML细胞系MOLM13、MV4-11以及THP-1均具有显著的增殖抑制作用(P<0.0001);1247825-37-1对于Flt3-ITD突变及非突变的AML患者原代细胞同样具有显著的增殖抑制作用,但对于Flt3-ITD非突变的原代细胞的抑制作用更强;1247825-37-1对AML细胞系的增殖抑制作用具有剂量依赖性,低剂量(2、4μmol/L)的1247825-37-1就能发挥作用;1247825-37-1能诱导上述AML细胞系发生凋亡,且具有显著的剂量依赖效应。结论USP7/USP47抑制剂1247825-37-1能够显著抑制Flt3-ITD突变及非突变AML细胞的增殖。Objective To investigate the effects of ubiquitin-specific protease(USP)7/47 inhibitor(Cat.No.1247825-37-1)on the proliferation and apoptosis of acute myeloid leukemia(AML)cells with or without internal tandem duplications of the Flt3 gene(Flt3-ITD).Methods ATP assay was used to detect the effects of 1247825-37-1 on the cell viability of two AML cell lines(MOLM13 and MV4-11)harboring Flt3-ITD mutation and one AML cell line(THP-1)without Flt3-ITD mutation as well as the primary Flt3-ITD-mutant and non-mutant AML cells from patient samples.Flow cytometry was used to detect the apoptosis of AML cell lines treated by different concentrations of 1247825-37-1.Results Compared with the control group,1247825-37-1 was able to significantly inhibit the proliferation of MOLM13,MV4-11 and THP-1 cells(P<0.0001).Besides,the cell viability of primary AML cells was also inhibited by 1247825-37-1,and a stronger inhibitory effect on non-mutant AML cells was observed.The USP7/USP47 inhibitor 1247825-37-1 could inhibit the proliferation of AML cells in a dose-dependent manner and a low dose(2 or 4μmol/L)of 1247825-37-1 would be effective.Moreover,1247825-37-1 was also able to efficiently induce the apoptosis of above AML cell lines in a dose-dependent manner.Conclusions The USP7/USP47 inhibitor 1247825-37-1 significantly inhibits the proliferation of AML cells with or without Flt3-ITD mutation.

关 键 词：急性髓系白血病 泛素特异性肽酶7 FLT3-ITD 增殖 AML细胞系 

分 类 号：R733.71[医药卫生—肿瘤]